Molecules from animals with exotic immune systems can be big business, as Andrew Joseph from STAT News points out. Pharmaceutical giant Sanofi recently bought a company focused on nanobodies, originally derived from camels, llamas and alpacas, for $4.8 billion.

Lampreys’ variable lymphocyte receptors (VLRs) are their version of antibodies, even though they look quite different in molecular terms. Research on VLRs and their origins may seem impractical. However, Cooper’s team has shown their utility as diagnostic tools, and his colleagues have been weaponizing them, possibly for use in cancer immunotherapy.

CAR-T cells have attracted attention for dramatic elimination of certain types of leukemias from the body and also for harsh side effects and staggering costs; see this opinion piece by Georgia Tech’s Aaron Levine. Now many research teams are scheming about how to apply the approach to other types of cancers. The provocative idea is: replace the standard CAR (chimeric antigen receptor) warhead with a lamprey VLR.

Imagine a shaker table, where kids can assemble a structure out of LEGO bricks and then subject it to a simulated earthquake. The objective is to design the most stable structure.

Biochemists face a similar task when they are attempting to design thermostable proteins, with heat analogous to shaking. Thermostable proteins, which do not become unfolded/denatured at high temperatures, are valuable for industrial processes.

Now imagine that these stable structures have to also perform a function. This is the two-part challenge of designing thermostable proteins. They have to maintain their physical structure, and continue to perform their function adequately, all at high temperatures.

Eric Ortlund and colleagues, working with Eric Gaucher at Georgia Tech*, have a new paper published in Structure, in which they examine different ways to achieve this goal in a component of the protein synthesis machinery, EF-Tu. This protein exists in both mesophilic bacteria, which live at around human body temperature, and thermophilic organisms (think: hot springs).

A previous analysis by Gaucher used the ASR technique (ancestral sequence reconstruction) to resurrect ancient, extinct EF-Tus and characterize them. It was shown that that ancestral EF-Tus were thermostable and functional. EF-Tu’s thermostability declined along with the environmental temperature; ancestral bacteria started off living in hot environments and those environments cooled off over millions of years.

In the new paper, Ortlund and first author Denise Okafor show that stable proteins generated by protein engineering methods do not always retain their functional capabilities. However, the ASR technique has a unique advantage, Ortlund says. By accounting for the evolutionary history of the protein, it preserves the natural motions required for normal protein function. Their results suggest that ASR could be used to engineer thermostability in other proteins besides EF-Tu.

Prions have a notorious reputation. They cause neurodegenerative disease, namely mad cow/Creutzfeld-Jakob disease. And the way these protein particles propagate – getting other proteins to join the pile – can seem insidious.

Yet prion formation could represent a protective response to stress, research from Emory University School of Medicine and Georgia Tech suggests.

A yeast protein called Lsb2, which can trigger prion formation by other proteins, actually forms a “metastable” prion itself in response to elevated temperatures, the scientists report.

Higher temperatures cause proteins to unfold; this is a major stress for yeast cells as well as animal cells, and triggers a “heat shock” response. Prion formation could be an attempt by cells to impose order upon an otherwise chaotic jumble of misfolded proteins, the scientists propose.

A glowing red clump can be detected in yeast cells containing a Lsb2 prion (left), because Lsb2 is hooked up to a red fluorescent protein. In other cells lacking prion activity (right), the Lsb2 fusion protein is diffuse.

“What we found suggests that Lsb2 could be the regulator of a broader prion-forming response to stress,” says Keith Wilkinson, PhD, professor of biochemistry at Emory University School of Medicine.

The scientists call the Lsb2 prion metastable because it is maintained in a fraction of cells after they return to normal conditions but is lost in other cells. Lsb2 is a short-lived, unstable protein, and mutations that keep it around longer increase the stability of the prions.

The Cell Reports paper was the result of collaboration between Wilkinson, Emory colleague Tatiana Chernova, PhD, assistant professor of biochemistry, and the laboratory of Yury Chernoff, PhD in Georgia Tech’s School of Biological Sciences.

“It’s fascinating that stress treatment may trigger a cascade of prion-like changes, and that the molecular memory of that stress can persist for a number of cell generations in a prion-like form,” Chernoff says.”Our further work is going to check if other proteins can respond to environmental stresses in a manner similar to Lsb2.” Read more

Scientists can improve protein-based drugs by reaching into the evolutionary past, a paper published this week in Nature Biotechnology proposes.

As a proof of concept for this approach, the research team from Emory, Children’s Healthcare of Atlanta and Georgia Tech showed how “ancestral sequence reconstruction” or ASR can guide engineering of the blood clotting protein known as factor VIII, which is deficient in the inherited disorder hemophilia A.

Structure of Factor VIII

Other common protein-based drugs include monoclonal antibodies, insulin, human growth hormone and white blood cell stimulating factors given to cancer patients. The authors say that ASR-based engineering could be applied to other recombinant proteins produced outside the human body, as well as gene therapy.

It has been possible to produce human factor VIII in recombinant form since the early 1990s. However, current factor VIII products still have problems: they don’t last long in the blood, they frequently stimulate immune responses in the recipient, and they are difficult and costly to manufacture.

Experimental hematologist and gene therapist Chris Doering, PhD and his colleagues already had some success in addressing these challenges by filling in some of the sequence of human factor VIII with the same protein from pigs.

“We hypothesized that human factor VIII has evolved to be short lived in the blood to reduce the risk of thrombosis,” Doering says. “And we reasoned that by going even farther back in evolutionary history, it should be possible to find more stable, potent relatives.”

Doering is associate professor of pediatrics at Emory University School of Medicine and Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta. The first author of the paper is former Molecular and Systems Pharmacology graduate student Philip Zakas, PhD.

ASR involves reaping the recent harvest of genome sequences from animals as varied as mice, cows, goats, whales, dogs, cats, horses, bats and elephants. Using this information, scientists reconstruct a plausible ancestral sequence for a protein in early mammals. They then tweak the human protein, one amino acid building block at a time, toward the ancestral sequence to see what kinds of effects the changes could have. Read more

A mechanism by which stress hormones inhibit the immune system, which appeared to be relatively new in evolution, may actually be hundreds of millions of years old.

A protein called the glucocorticoid receptor or GR, which responds to the stress hormone cortisol, can take on two different forms to bind DNA: one for activating gene activity, and one for repressing it. In a paper published Dec. 28 in PNAS, scientists show how evolutionary fine-tuning has obscured the origin of GRâ€™s ability to adopt different shapes.

â€œWhat this highlights is how proteins that end up evolving new functions had those capacities, because of their flexibility, at the beginning of their evolutionary history,â€ says lead author Eric Ortlund, PhD, associate professor of biochemistry at Emory University School of Medicine.

GR is part of a family of steroid receptor proteins that control cellsâ€™ responses to hormones such as estrogen, testosterone and aldosterone. Our genomes contain separate genes encoding each one. Scientists think that this family evolved by gene duplication, branch by branch, from a single ancestor present in primitive vertebrates. Read more

This complex diagram, showing the gene segments that encode lamprey variable lymphocyte receptors, comes from a recent PNAS paper published by Emory’s Max Cooper and his colleagues along with collaborators from Germany led by Thomas Boehm. Lampreys have moleculesÂ that resemble our antibodies in function, but theyÂ look very different at the protein level. The study of lamprey immunityÂ provides hints to how the vertebrate immune system has evolved.

Gaucher and Ortlund teamed up to “resurrect” ancient versions of the enzyme uricase, in search of an explanation for why humans develop gout. Yong explains:

The substance responsible for the condition [gout] is uric acid, which is normally expelled by our kidneys, via urine. But if thereâ€™s too much uric acid in our blood, it doesnâ€™t dissolve properly and forms large insoluble crystals that build up in our joints. That explains the http://www.raybani.com/ painful swellings. High levels of uric acid have also been linked to obesity, diabetes, and diseases of the heart, liver and kidneys. Most other mammals donâ€™t have this problem. In their bodies, an enzyme called uricase converts uric acid into other substances that can be more easily excreted.

Uricase is an ancient invention, one thatâ€™s shared by bacteria and animals alike. But for some reason, apes have abandoned it. Our uricase gene has mutations that stop us from making the enzyme at all. Itâ€™s a â€œpseudogeneâ€â€”the biological version of a corrupted computer file. And itâ€™s the reason that our blood contains 3 to 10 times more uric acid than that of other mammals, predisposing us to gout.

“Our role* on the project was to solve the three dimensional structure of this enzyme using X-ray crystallography to figure out how these ancient mutations led to a decline in uricase activity in humans and apes,” Ortlund says. “We were interested in how this enzyme lost function, and for the future, how we can restore function to this enzyme to create a more â€œhuman-likeâ€ (and thus less immunogenic) protein than the current available bacterial or baboon-pig uricase chimeras.”

(There’s even a patent on this ancient uricase as a potential treatment for gout, and a start-up company named General Genomics)

Their paper also explores what advantage humans might have gained from losing functional uricase. The proposal is: by disabling uricase, ancient primates became more efficient at Ray Ban outlet turning fructose, the sugar found in fruit, into fat. Their results provide some support for the “thrifty gene hypothesis:” the idea that humans are evolutionarily adapted to being able to survive an erratic food supply, which is not so great now that people in developed countries have access to lots of food. The authors write:

The loss of uricase may have provided a survival advantage by amplifying the effects of fructose to enhance fat stores, and by the ability of uric acid to stimulate foraging, while also increasing blood pressure in response to salt. Thus, the loss of uricase may represent the first example of a â€œthrifty geneâ€ to explain the current epidemic of obesity and diabetes, except that it is the loss of a gene, and not the acquisition of a new gene, that has ray ban da sole outlet increased our susceptibility to these conditions.Â

Studying lampreys allows biologists to envision the evolutionary past, because they represent an early offshoot of the evolutionary tree, before sharks and fish. Despite their inconspicuous appearance, lampreys have a sophisticated immune system with three types of white blood cell that resemble our B and T cells, researchers have discovered.

Scientists at Emory University School of Medicine and the Max Planck Institute of Immunology and Epigenetics in Freiburg have identified a type of white blood cell in lampreys analogous to the “gamma delta T cells” found in mammals, birds and fish. Gamma delta T cells have specialized roles defending the integrity of the skin and intestines, among other functions.

The results are published in the journalÂ Nature. The finding follows anÂ earlier studyÂ showing that cells resembling two main types of white blood cells, B cells and T cells, are present in lampreys.

Every time scientists identify genetic risk factors for a human disease or a personality trait, it seems like more weight accumulates on the “nature” side of the grand balance between nature and nurture.

That’s why it’s important to remember how much prenatal and childhood experiences such as education, nutrition, environmental exposures and stress influence later development.

At the Emory/Georgia Tech Predictive Health Symposium in December, biologist Victor Corces outlined this concept using a particularly evocative example: bees. A queen bee and a worker bee share the same DNA, so the only thing that determines whether an insect will become the next queen is whether she consumes royal jelly.

â€œThe past is difficult to recover because it was built on the foundation of its own history, one irrevocably different from that of the present and its many possible futures.â€

Whoa. This quote comes from a recent Nature paper. How did studying the protein that helps cells respond to the stress hormone cortisol inspire such philosophical language?

Biochemist Eric Ortlund at Emory and collaborator Joe Thornton at the University of Oregon specialize in â€œresurrectingâ€and characterizing ancient proteins. They do this by deducing how similar proteins from different organisms evolved from a common root, mutation by mutation. Sort of like a word ladder puzzle.

Ortlund and Thornton have been studying the glucocorticoid receptor, a protein that binds the hormone cortisol and turns on genes in response to stress. The glucocorticoid receptor is related to the mineralocorticoid receptor, which binds hormones such as aldosterone, a regulator of blood pressure and kidney function.

If these receptors have a common ancestor, you can model each step in the transformation that led from the ancestor to each descendant. But Ortlund says that protein evolution isnâ€™t like a word ladder puzzle, which can be turned upside-down: â€œYou canâ€™t rewind the tape of life and have it take the same path.â€

The reason: Mutations arise amidst a background of selective pressure, and mutations in one part of a protein set the stage for whether other ones will be viable. The researchers describe this as an â€œepistatic rachetâ€.

Mutations that occurred during the transformation between the ancestral protein (green) and its descendant (orange) would clash if put back to their original position.

This work highlights the increasing number of structural biologists like Ortlund, Christine Dunham, Graeme Conn and Xiaodong Cheng at Emory. Structural biologists use techniques such as X-ray crystallography to figure out how the parts of biologyâ€™s machines fit together. Recently Emory has been investing in the specialized equipment necessary to conduct X-ray crystallography.

As part of his future plans, Ortlund says he wants to go even further back in evolution, to examine the paths surrounding the estrogen receptor, which is also related to the glucocorticoid receptor.

Besides giving insight into the mechanisms of evolution, Ortlund says his research could also help identify drugs that activate members of this family of receptors more selectively. This could address side effects of drugs now used to treat cancer such as tamoxifen, for example, as well as others that treat high blood pressure and inflammation.